Patients with amnestic mild cognitive impairment (MCI) often have a compromised quality of life (QOL). Cognitive impairment is a major contributor to decrements in QOL and progression of MCI often leads to loss of independence and withdrawal from social participation. MCI, in many patients, is an early expression of neurodegenerative disease. Patients with MCI frequently convert to Alzheimer's disease (AD) (12-16 percent by some estimates per year). Treatments for MCI are of limited scope and availability and of limited effectiveness. Thus, there is great need for treatments that can improve cognition and extend QOL in patients with MCI. Early intervention (prior to the development of dementia) is more likely to successfully treat this population. We propose to investigate the effect of a non-invasive and safe intervention that should have direct influence on brain systems underlying AD, transcutaneous vagal nerve stimulation (tVNS). This promising approach has not yet been studied in patients with MCI. The hippocampus is a structure that deteriorates in AD. Further, studies have suggested that the locus coeruleus (LC), the brainstem nucleus that is the brain's sole source of norepinephrine (NE), may be one of the first structures that deteriorates in patients with AD. The release of NE in the hippocampus and frontal lobes has an important role in cognition and is critical in mediating memory and attention. The ascending portions of the vagus nerve form synapses within the nucleus of the solitary tract, which projects to the LC and to the hippocampus. The LC also projects directly to the hippocampus. Thus, vagal nerve stimulation (VNS) may ameliorate symptoms of MCI. We have demonstrated, in patients with epilepsy, that VNS improves memory; however, VNS has not been used to treat patients with MCI. VNS can now be performed without surgery by transcutaneous stimulation of the auricular branch with electrodes on the external ear. tVNS has the potential to improve cognition and may even alter the course of decline in patients with MCI. We will employ a multimodal MRI-based neuroimaging approach combined with comprehensive and targeted cognitive testing to assess changes with tVNS in cognition in patients with MCI. We will evaluate the effects of tVNS on 60 patients who have been diagnosed with MCI. To maximize statistical power, we will employ a cross-over design with tVNS and control stimulation conditions (stimulating an area on the external ear that does not have nerve endings that connect to the vagus). Very little in the way of mechanistic data or understanding of individual differences in response to tVNS in MCI/AD has been published. Thus, this is a necessary study to evaluate the potential utility of tVNS to enhance cognitive performance in patients with MCI. These data may serve as a platform for supporting the development of a clinical trial with this technology.

Public Health Relevance

Alzheimer's disease (AD) is a major source of cognitive and quality of life (QOL) decline in older people and mild cognitive impairment (MCI) is often the first indicator of AD. Intervening early (e.g., at the MCI stage) in AD is a good strategy to preserving cognitive and brain function in these patients. We will examine the effects of a non-invasive and safe treatment option, transcutaneous vagal nerve stimulation (tVNS), that directly effects brain structures impacted early in the AD process in patients with MCI.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Mclinden, Kristina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Medicine
United States
Zip Code